Background: Sex hormone may play a role in lung cancer pathophysiology. We aimed to evaluate if androgen pathway manipulation (APM) is associated with better survival in patients with lung cancer, and how finasteride, a 5-alpha reductase inhibitor, impacts androgen receptor (AR) activation and growth of lung cancer cells. Methods: In this retrospective hospital-based cohort study, we screened all men with lung cancer diagnosed during the period from January 2006 to December 2021. APM exposure was defined as using antiandrogens, 5-alpha reductase inhibitors, or gonadotropin-releasing hormone agonists for > 30 days after lung cancer diagnosis. The in vitro study was conducted on A549 lung cancer cells; while the tumor xenograft model was conducted on BALB/c nude mice. Results: Among 4744 men with lung cancer, 98 (2.1%) were identified as having APM exposure. The majority of patients (73.5%) received 5-alpha reductase inhibitors. The patients with APM exposure were older (71.5 vs. 67.0, p < 0.001), had a higher proportion of having prostate cancer (27.6% vs. 1.4%, p < 0.001), and had a smaller proportion of having metastatic lung cancer (41.8% vs. 54.0%, p = 0.003), compared to those without APM exposure. In multivariable Cox proportional hazards analysis, patients with APM exposure experienced better OS compared to those without exposure (Hazard ratio 0.57; 95% CI, 0.44–0.73, p < 0.001). In in vitro study, we illustrated that AR protein stimulated the cell proliferation of A549 cells. Finasteride reduced the AR protein expression and inhibited A549 cell growth. Finasteride promoted ubiquitination and degradation of AR protein and therefore interfered the stability of AR protein. Furthermore, finasteride inhibited cell cycle progression and promoted apoptosis of A549 cells. The in vivo results also supported the inhibition effect of finasteride on lung cancer growth. Conclusions: APM was associated with better OS in male patients with lung cancer. Finasteride interfered with the stability of AR and inhibited A549 lung cancer cell growth. Our findings indicated an oncogenic role of AR on lung cancer which may provide potential therapeutic and targets for lung cancer. The inhibition effect of finasteride on lung cancer might be of benefit for future treatment strategies, prevention and control.